Frontotemporal dementia is a fatal neurodegenerative disease that results in progressive decline in behavior, executive function, and language. Currently, there are no effective treatments. Recent advances, however, have led to a greater understanding of the most common pathological form of the disease, called frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U). In 2006, the major protein in the hallmark ubiquitinated inclusions of FTLD-U was identified as TAR DMA binding protein 43 (TDP-43). The function of TDP-43 is largely unknown. However, several lines of evidence indicate a role in the regulation of gene expression. TDP-43 binds DNA and RNA, regulating through these interactions the temporal and tissue-specific expression of some genes, as well as the splicing of others. Moreover, physiologic TDP-43 is nuclear, where it associates with heterogeneous ribonucleoproteins with well-known splicing activities. This research proposal is designed around the hypothesis that through aberrant activity of TDP-43, dysregulation of gene expression is a key disease mechanism in FTLD-U. Genome-wide approaches will be employed to evaluate this hypothesis. The following are the proposal's specific aims: 1. Obtain and analyze genome-wide expression profiles of FTLD-U at the mRNA and microRNA levels. 2. Identify DNA binding partners of TDP-43 in cell culture models and in FTLD-U using chromatin immunoprecipitation of TDP-43 followed by microarray analysis (ChlP-on-chip). 3. Characterize the relationship of specific microRNAs and TDP-43 to changes in mRNA expression. 4. Extend techniques developed in the study of FTLD-U to other diseases characterized by the accumulation of pathologic TDP-43. RELEVANCE (See instructions): Frontotemporal dementia is the second-most common cause of dementia in individuals under age 65. Understanding key genes dysregulated in this disease could lead to the development of targeted therapies.